Transplantation is a proven method for replacement or repair of damaged tissue; however, the survival of the engrafted tissue and the ultimate success of the transplant rests on whether the transplant is accepted by the host. Several strategies have emerged over the years that would improve the use of autologous cells in transplantation therapy for CNS disease and injury: 1 ) ex vivo gene therapy, where a therapeutic factor is secreted by a transplant of autologous cells, 2) transplantation of adult stem cells isolated from various tissues, and 3) transplantation of CNS cell types derived from stem cells such as induced pluripotent stem cells. There are drawbacks to each of these strategies: transplanted non-CNS cells cannot functionally integrate and respond to the in vivo CNS environment, and transplanted bona fide CNS cells derived from progenitors may retain some remnant of their proliferative capability and form a tumor. We have identified a combination of transactivating factors and culture conditions for human and rat fibroblasts that result in cells with neuronal characteristics similar to those described for mouse induced neural cells (INCs). INCs generated from fetal or adult rat and human cells display the morphological, marker expression/distribution, and electrophysiological properties of neurons in culture, but nothing is known about INC function when introduced into the living mammalian CNS. The objective of this proposal is to ascertain the survival, differentiation into CNS cell types, and capacity for functional integration of engrafted autologous rat and non-autologous human INCs into the newborn and adult rat CNS. This pilot study will determine the effect of INCs on the CNS and the effect of the CNS on INCs - both new and equally important unanswered questions. The innovation of INCs as possible neural transplants is that they theoretically combine the best features of current transplantation strategies, namely, the safety of cells with stringent growth control combined with the potential capacity to functionally integrate and respond to the CNS environment. The experiments proposed are designed to define the potential of transdifferentiated neural cells or transneurons - in their native environment. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine if neuron-like cells called INCs, produced directly from skin cells, can reproduce the features of bona fide neurons after transplantation into the mammalian central nervous system (CNS). By determining how INCs survive transplantation, integrate into brain tissue, and connect with brain cells already present in the CNS, this project will significantly impact public health and providin a roadmap for future treatments where patients with neurological disease or brain/spinal cord injury will receive their own skin cells - converted to neurons - as a therapeutic transplant.